Ischemic acute kidney injury (AKI) is a devastating clinical complication resulting in renal tubular death and systemic inflammation. Patients with kidney dysfunction have elevated plasma catecholamine levels. In addition to causing hypertension, catecholamines produce an inflammatory response in sepsis and multi-organ dysfunction.
Renalase is a 38 kDa flavin adenine dinucleotide (FAD)-dependent amine oxidase synthesized and secreted by the renal proximal tubules (Xu et al., 2005, J Clin Invest 115: 1275-1280). Renalase degrades circulating catecholamines and regulates systemic blood pressure in rodents and humans (Desir, 2012, Pediatr Nephrol 27: 719-725). Plasma catecholamines and systemic blood pressure are elevated in patients with chronic kidney dysfunction or end stage renal insufficiency (Schlaich, 2009, J Am Soc Nephrol 20: 933-939). Recent studies suggest that renalase deficiency in patients with chronic renal insufficiency leads to increased plasma catecholamine levels and systemic blood pressure (Desir, 2012, Pediatr Nephrol 27: 719-725; Desir, 2009, Kidney Int 76: 366-370; Desir, 2011, Curr Opin Nephrol Hypertens 20: 31-36; Li et al., 2008, Circulation 117: 1277-1282).
In addition to regulating blood pressure, renalase may protect against inflammatory tissue injury by metabolizing catecholamines Catecholamines via activation of leukocyte alpha adrenergic receptors directly cause inflammation in sepsis and multi-organ dysfunction (Grisanti et al., 2011, J Pharmacol Exp Ther 338: 648-657; Miksa et al., 2009, PLoS One 4: e5504). Indeed, patients with chronic renal insufficiency show increased markers of inflammation that contribute directly to increased morbidity and mortality (Kaysen and Eiserich, 2003, Semin Dial 16: 438-446). In mice, renalase deficiency resulted in exacerbated cardiac IR injury and exogenous renalase administration reduced myocardial necrosis (Wu et al., 2011, Kidney Int 79: 853-860).
Ischemic acute kidney injury is a major problem for patients subjected to major surgical procedures involving the kidney, liver, heart or aorta (Chertow et al., 2005, J Am Soc Nephrol 16: 3365-3370). Renal ischemia reperfusion (IR) injury is a frequent cause of clinical AKI with the incidence of AKI exceeding 50% after major cardiac, hepatobiliary or aortic surgery (Bove et al., 2004, J Cardiothorac Vasc Anesth 18: 442-445; Elapavaluru and Kellum, 2007, Acta Clin Belg Supp! 326-331). Furthermore, ischemic AKI is frequently complicated by multi-organ dysfunction, systemic inflammation, sepsis and death (Jones and Lee, 2008, Best Pract Res Clin Anaesthesiol 22: 193-208). Unfortunately, there are no proven therapies to prevent or treat AKI in the perioperative setting (Jo et al., 2007, Clin J Am Soc Nephrol 2: 356-365).
Thus, there is a need in the art for compositions and methods for the treatment and prevention of renal injury, such as AKI. The present invention addresses this unmet need in the art.